The naturally occurring prostaglandin, PGF2a, is a twenty-carbon (C-20) unsaturated fatty acid derived from arachidonic acid. Using standard prostaglandin nomenclature, PGF2a possesses alpha-hydroxyl groups at both C9 and at C11 on the cyclopentane ring, a cis double bond between C5 and C6, and a trans double bond between C13 and C14. Thus PGF2ahas the following structure: 
Analogs of PGF2aare useful for the treatment of several medical conditions including, for example: ocular disorders, such as glaucoma; circulatory disorders, gastrointestinal disorders; fertility control; and bone disorders, such as osteoporosis. Information regarding the biological effects of Prostaglandin F analogs is disclosed in the following references: PCT Publication No. WO 99/12895, 1999; PCT Publication No. WO 99/12896, 1999; PCT Publication No. WO 99/12898; Chem. Abstr. 1999, 194116 xe2x80x9cMolecular mechanisms of diverse actions of prostanoid receptorsxe2x80x9d, Biochimica et Biophysica Acta, 1259 (1995) 109-120; U.S. Pat. No. 3,776,938 issued to Bergstrom, S., and Sjovall, J., Dec. 4, 1973; U.S. Pat. No. 3,882,241 issued to Pharriss, G., May 6, 1975; G.B. Patent No. 1,456,512 (1976) issued to Pfizer Inc., Bundy, G. L.; Lincoln, F. H., xe2x80x9cSynthesis of 17-Phenyl-18,19,20-trinor prostaglandins I. The PGI Seriesxe2x80x9d, Prostaglandins Vol. 9 (1975) pp. 1-4.; CRC Handbook of Eicosanoids: Prostaglandins and Related Lipids Vol. 1, Chemical and Biochemical Aspects, Parts A and B, A. L. Willis, eds., CRC Press (1987); Liljebris, C.; et. al. xe2x80x9cDerivatives of 17-Phenyl-18,19,20-trinorprostaglandin F2a Isopropyl Ester: Potential Antiglaucoma Agentsxe2x80x9d, Journal of Medicinal Chemistry Vol. 38, (1995), pp. 289-304; Collins, P. W.; Djuric, S. W. xe2x80x9cSynthesis of Therapeutically Useful Prostaglandin and Prostacyclin Analogsxe2x80x9d, Chemical Reviews 93 (1993), pp. 1533-1564.
All naturally occurring prostaglandins, including PGF2a, possess a carboxylic acid moiety at the C1 position. The carboxylic acid moiety is a site for metabolic degradation by beta oxidation, which contributes to the rapid metabolism of the naturally occurring prostaglandins. Attempts to prevent beta oxidation by modifying the carboxylic acid moiety at the 1 position as an ester moiety, an amide moiety, a sulfonamide moiety, and as a tetrazole moiety are known in the art (See e.g. PCT Publication No. WO 99/12895, 1999; PCT Publication No. WO 99/12896, 1999; PCT Publication No. WO 99/12898).
However, such modifications have either resulted in only modest increases in half-life (such as the esters) or resulted in compounds with diminished potency.
Prostaglandin F analogs wherein C1, itself is replaced with a heteroatom have also been described in the art. For example, PGF analogs containing a sulfonic acid moiety at C1, (The chemistry of prostaglandins containing the sulfo group. Iguchi, Y.; Kori, S.;
Hayashi, M. J Org. Chem., 40, pp. 521-523 1975) and PGF analogs containing a phosphonic acid moiety at C, (The Synthesis of dimethylphosphonoprostaglandin analogs, Kluender, H. C. and Woessner, W. Prostaglandins and Medicine, 2: pp.441-444, 1979) have been disclosed. However, such compounds suffer from significantly diminished potency.
Further research in the area of heteroatomxe2x80x94containing C1, replacements has been hampered by the lack of a general synthetic route to advanced or key intermediates that would allow for the rapid preparation of a multitude of variants to replace C1. The Corey route to prostaglandins was specifically designed for a carboxcyclic acid moiety, and modifications which create reagents with relatively acidic protons are either incompatible with this route or cause significant optimization of this difficult step for each new C1 replacement. Syntheses of Prostaglandin F analogs via the Corey route are described in the following references: Corey, E. J.; Weinshenker, N. M.; Schaaf, T. K.; Huber, W J Am. Chem. Soc., 1969, 91, 5675 and Corey, E. J.; Schaaf, T. K.; Huber, W; Koelliker, U.; Weinshenker, N. M.; J. Am. Chem. Soc., 1970, 92, 397.
Thus, while a few Prostaglandin F analogs wherein C1 has been replaced with a heteroatomxe2x80x94containing moiety have been disclosed, there is a continuing need for suitable C1 replacements that result in potent, selective Prostaglandin F analogs for the treatment of a variety diseases and conditions.
The invention provides novel Prostaglandin F analogs. In particular, the present invention is directed to compounds having a structure according to the following formula: 
wherein R1, R2, X, Y, V, a, b, W, and Z are defined below.
This invention also includes optical isomers, diastereomers and enantiomers of the formula above, and pharmaceuticallyxe2x80x94acceptable salts, biohydrolyzable amides, esters, and imides thereof.
The compounds of the present invention are useful for the treatment of a variety of diseases and conditions, such as bone disorders and glaucoma. Accordingly, the invention further provides pharmaceutical compositions comprising these compounds. The invention still further provides methods of treatment for bone disorders and glaucoma using these compounds or compositions containing them.
The invention is directed to novel 2-decarboxy-2-phosphinico Prostaglandin F analogs, pharmaceutical compositions comprising these compounds, and methods of treating a variety of disorders by administering these compounds.
Definitions and Usage of Terms
xe2x80x9cAlkylxe2x80x9d is a saturated or unsaturated hydrocarbon chain. Unless otherwise specified (e.g. see xe2x80x9cC4 alkylxe2x80x9d, xe2x80x9cC1, alkylxe2x80x9d, xe2x80x9cCm alkylxe2x80x9d and xe2x80x9cCp alkylxe2x80x9d below), alkyl chains have 1 to 18 carbon atoms, preferably 1 to 12, more preferably 1 to 6, more preferably still 1 to 4 carbon atoms. Alkyl chains may be straight or branched. Preferred branched alkyl have one or two branches, preferably one branch. Unsaturated alkyl have one or more double bonds and/or one or more triple bonds. Preferred unsaturated alkyl have one or two double bonds or one triple bond, more preferably one double bond. Alkyl chains may be unsubstituted or substituted with from 1 to about 4 substituents unless otherwise specified. Preferred substituted alkyl are mono-, di-, or trisubstituted. Preferred alkyl substituents include cyano, halo, hydroxy, aryl (e.g., phenyl, tolyl, alkyloxphenyl, alkyloxycarbonylphenyl, halophenyl), heterocyclyl, and heteroaryl.
xe2x80x9cAromatic ringxe2x80x9d is an aromatic hydrocarbon ring system. Aromatic rings are monocyclic or fused bicyclic ring systems. Monocyclic aromatic rings contain from about 5 to about 10 carbon atoms, preferably from 5 to 7 carbon atoms, and most preferably from 5 to 6 carbon atoms in the ring. Bicyclic aromatic rings contain from 8 to 12 carbon atoms, preferably 9 or 10 carbon atoms in the ring. Aromatic rings may be unsubstituted or substituted with from 1 to about 4 substituents on the ring. Preferred aromatic ring substituents include: halo, cyano, lower alkyl, heteroalkyl, haloalkyl, phenyl, phenoxy or any combination thereof. More preferred substituents include lower alkyl, cyano, halo and haloalkyl.
xe2x80x9cBiohydrolyzable amidexe2x80x9d is an amide moiety that does not interfere with the therapeutic activity of the compound, or that is readily metabolized by a human or other mammal.
xe2x80x9cBiohydrolyzable esterxe2x80x9d is an ester moiety that does not interfere with the therapeutic activity of the compound, or that is readily metabolized by a human or other mammal.
xe2x80x9cBiohydrolyzable imidexe2x80x9d is an imide moiety that does not interfere with the therapeutic activity of the compound, or that is readily metabolized by a human or other mammal.
xe2x80x9cC4 alkylxe2x80x9d is an alkyl chain having 4 carbon member atoms. C4 alkyl may be staurated or unsaturated with one or two double bonds (cis or trans), one triple bond, or one double bond (cis or trans) and one triple bond. Preferred unsaturated C4 alkyl have one double bond. C4 alkyl may be unsubstituted or substituted with one or two substituents. Preferred substituents include lower alkyl, lower heteroalkyl, cyano, halo, and haloalkyl. More preferred substituents are cyano and halo.
xe2x80x9cC1 alkylxe2x80x9d is an alkyl chain having xe2x80x9c1xe2x80x9d carbon member atoms. C1 alkyl may be staurated or unsaturated with one trans double bond or one triple bond. Preferred C1 alkyl are saturated. Preferred unsaturated C1 alkyl have one trans double bond. C1 alkyl may be unsubstituted or substituted with from 1 to about 3 substituents. Preferred substituents include lower alkyl, lower heteroalkyl, cyano, halo, and haloalkyl.
xe2x80x9cCm alkylxe2x80x9d is an alkyl chain having xe2x80x9cmxe2x80x9d carbon member atoms. Cm alkyl may be staurated or unsaturated with one trans double bond or one triple bond. Preferred unsaturated Cm alkyl have one triple bond. Cm alkyl may be unsubstituted or substituted with one or two substituents. Preferred Cm alkyl are unsubstituted. Preferred substituents include lower alkyl, lower heteroalkyl, cyano, halo, and haloalkyl.
xe2x80x9cCp alkylxe2x80x9d is an alkyl chain having xe2x80x9cpxe2x80x9d carbon member atoms. Cp alkyl may be staurated or unsaturated with one trans double bond or one triple bond. Preferred unsaturated Cm alkyl have one triple bond. Unsaturated Cp alkyl are unsubstituted. Saturated Cp alkyl may be unsubstituted or substituted with one or two substituents. Preferred Cp alkyl are unsubstituted. Preferred substituents include lower alkyl, lower heteroalkyl, cyano, halo, and haloalkyl.
xe2x80x9cCarbocyclic aliphatic ringxe2x80x9d is a saturated or unsaturated hydrocarbon ring. Carbocyclic aliphatic rings are not aromatic. Carbocyclic aliphatic rings are monocyclic, or are fused, spiro, or bridged bicyclic ring systems. Monocyclic carbocyclic aliphatic rings contain from about 4 to about 10 carbon atoms, preferably from 4 to 7 carbon atoms, and most preferably from 5 to 6 carbon atoms in the ring. Bicyclic carbocyclic aliphatic rings contain from 8 to 12 carbon atoms, preferably from 9 to 10 carbon atoms in the ring. Carbocyclic aliphatic rings may be unsubstituted or substituted with from 1 to about 4 substituents on the ring. Preferred carbocyclic aliphatic ring substituents include: halo, cyano, lower alkyl, heteroalkyl, haloalkyl, phenyl, phenoxy or any combination thereof More preferred substituents include halo and haloalkyl. Preferred carbocyclic aliphatic rings include cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.
xe2x80x9cHaloxe2x80x9d is fluoro, chloro, bromo or iodo. Preferred halo are fluoro, chloro and bromo; more preferred are chloro and fluoro.
xe2x80x9cHaloalkylxe2x80x9d is a straight, branched, or cyclic hydrocarbon substituted with one or more halo substituents. Preferred haloalkyl are C1xe2x80x94C12; more preferred are C1xe2x80x94C6; more preferred still are C1xe2x80x94C3. Preferred halo substituents are fluoro and chloro. The most preferred haloalkyl is trifluoromethyl.
xe2x80x9cHeteroalkylxe2x80x9d is a saturated or unsaturated chain containing carbon and at least one heteroatom, wherein no two heteroatoms are adjacent. Heteroalkyl chains contain from 1 to 18 member atoms (carbon and heteroatoms) in the chain, preferably 1 to 12, more preferably 1 to 6, more preferably still 1 to 4. Heteroalkyl chains may be straight or branched. Preferred branched heteroalkyl have one or two branches, preferably one branch. Preferred heteroalkyl are saturated. Unsaturated heteroalkyl have one or more double bonds and/or one or more triple bonds. Preferred unsaturated heteroalkyl have one or two double bonds or one triple bond, more preferably one double bond. Heteroalkyl chains may be unsubstituted or substituted with from 1 to about 4 substituents unless otherwise specified. Preferred heteroalkyl are unsubstituted. Preferred heteroalkyl substituents include halo, aryl (e.g., phenyl, tolyl, alkyloxyphenyl, alkyloxycarbonylphenyl, halophenyl), heterocyclyl, heteroaryl. For example, alkyl chains substituted with the following substituents are heteroalkyl: alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy, pentoxy), aryloxy (e.g., phenoxy, chlorophenoxy, tolyloxy, methoxyphenoxy, benzyloxy, alkyloxycarbonylphenoxy, acyloxyphenoxy), acyloxy (e.g., propionyloxy, benzoyloxy, acetoxy), carbamoyloxy, carboxy, mercapto, alkylthio, acylthio, arylthio (e.g., phenylthio, chlorophenylthio, alkylphenylthio, alkoxyphenylthio, benzylthio, alkyloxycarbonylphenylthio), amino (e.g., amino, mono- and di- C1xe2x80x94C3 alkanylamino, methylphenylamino, methylbenzylamino, C1xe2x80x94C3 alkanylamido, carbamamido, ureido, guanidino).
xe2x80x9cHeteroatomxe2x80x9d is a nitrogen, sulfur, or oxygen atom. Groups containing more than one heteroatom may contain different heteroatoms. As used herein, halogens are not heteroatoms.
xe2x80x9cHeterocyclic aliphatic ringxe2x80x9d is a saturated or unsaturated ring containing carbon and from 1 to about 4 heteroatoms in the ring, wherein no two heteroatoms are adjacent in the ring and no carbon in the ring that has a heteroatom attached to it also has a hydroxyl, amino, or thiol group attached to it. Heterocyclic aliphatic rings are not aromatic. Heterocyclic aliphatic rings are monocyclic, or are fused or bridged bicyclic ring systems. Monocyclic heterocyclic aliphatic rings contain from about 4 to about 10 member atoms (carbon and heteroatoms), preferably from 4 to 7, and most preferably from 5 to 6 member atoms in the ring. Bicyclic heterocyclic aliphatic rings contain from 8 to 12 member atoms, preferably 9 or 10 member atoms in the ring. Heterocyclic aliphatic rings may be unsubstituted or substituted with from 1 to about 4 substituents on the ring. Preferred heterocyclic aliphatic ring substituents include: halo, cyano, lower alkyl, heteroalkyl, haloalkyl, phenyl, phenoxy or any combination thereof. More preferred substituents include halo and haloalkyl. Preferred heterocyclic aliphatic rings include piperzyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and piperdyl.
xe2x80x9cHeteroaromatic ringxe2x80x9d is an aromatic ring system containing carbon and from 1 to about 4 heteroatoms in the ring. Heteroaromatic rings are monocyclic or fused bicyclic ring systems. Monocyclic heteroaromatic rings contain from about 5 to about 10 member atoms (carbon and heteroatoms), preferably from 5 to 7, and most preferably from 5 to 6 in the ring. Bicyclic heteroaromatic rings contain from 8 to 12 member atoms, preferably 9 or 10 member atoms in the ring. Heteroaromatic rings may be unsubstituted or substituted with from 1 to about 4 substituents on the ring. Preferred heteroaromatic ring substituents include: halo, cyano, lower alkyl, heteroalkyl, haloalkyl, phenyl, phenoxy or any combination thereof. More preferred substituents include halo, haloalkyl, and phenyl. Preferred heteroaromatic rings include thienyl, thiazolo, purinyl, pyrimidyl, pyridyl, and furanyl. More preferred heteroaromatic rings include thienyl, furanyl, and pyridyl. The most preferred heteroaromatic ring is thienyl.
xe2x80x9cLower alkylxe2x80x9d is an alkyl chain comprised of 1 to 4, preferably 1 to 3 carbon member atoms, more preferably 1 or 2 carbon member atoms. Lower alkyl may be saturated or unsaturated. Preferred lower alkyl are saturated. Lower alkyl may be unsubstituted or substituted with one or about two substituents. Preferred substituents on lower alkyl include cyano, halo, triflouromethyl, and hydroxy.
xe2x80x9cLower heteroalkylxe2x80x9d is a heteroalkyl chain comprised of 1 to 4, preferably 1 to 3 member atoms, more preferably 1 to 2 member atoms. Lower heteroalkyl contain one or two heteroatom member atoms. Preferred lower heteroalkyl contain one heteroatom member atom. Lower heteroalkyl may be saturated or unsaturated. Preferred lower heteroalkyl are saturated. Lower heteroalkyl may be unsubstituted or substituted with one or about two substituents. Preferred substituents on lower heteroalkyl include cyano, halo, triflouromethyl, and hydroxy.
xe2x80x9cM4 heteroalkylxe2x80x9d is a heteroalkyl chain having 4 member atoms. M4 heteroalkyl contain one or two heteroatom member atoms. M4 heteroalkyl containing 1 heteroatom member atom may be saturated or unsaturated with one double bond (cis or trans) or one triple bond. Preferred M4 heteroalkyl containing 2 heteroatom member atoms are saturated. Preferred unsaturated M4 heteroalkyl have one double bond. M4 heteroalkyl may be unsubstituted or substituted with one or two substituents. Preferred substituents include lower alkyl, lower heteroalkyl, cyano, halo, and haloalkyl.
xe2x80x9cM1 heteroalkylxe2x80x9d is a heteroalkyl chain having xe2x80x9c1 xe2x80x9d member atoms. M1 heteroalkyl contain one or two heteroatom member atoms. Preferred M1 heteroalkyl have one heteroatom member atom. M1 heteroalkyl may be saturated or unsaturated with one trans double bond or one triple bond. Preferred M1 heteroalkyl are saturated. M1 heteroalkyl may be unsubstituted or substituted with from 1 to about 3 substituents. Preferred substituents include lower alkyl, lower heteroalkyl, and haloalkyl.
xe2x80x9cMn heteroalkylxe2x80x9d is a heteroalkyl chain having xe2x80x9cnxe2x80x9d member atoms. Mn heteroalkyl contain one heteroatom member atom. Mn heteroalkyl may be staurated or unsaturated with one triple bond. Preferred Mn heteroalkyl are saturated. Mn heteroalkyl may be unsubstituted or substituted with one or two substituents. Preferred substituents include lower alkyl, lower heteroalkyl, and haloalkyl.
xe2x80x9cMq heteroalkylxe2x80x9d is a heteroalkyl chain having xe2x80x9cqxe2x80x9d member atoms. Mq heteroalkyl contain one heteroatom member atom. Mq heteroalkyl are staurated. Mq heteroalkyl may be unsubstituted or substituted with one or two substituents. Preferred substituents include lower alkyl, lower heteroalkyl, cyano, halo, and haloalkyl.
xe2x80x9cMember atomxe2x80x9d refers to a polyvalent atom (C, O, N, or S atom) in a chain or ring system that continues the chain or ring system. For example, in benzene the six carbon atoms are member atoms and the six hydrogen atoms are not member atoms.
xe2x80x9cPharmaceuticallyxe2x80x94acceptable saltxe2x80x9d refers to a cationic salt formed at any acidic (e.g., hydroxamic acid) group, or an anionic salt formed at any basic (e.g., amino) group. Such salts are well known in the art. See e.g: World Patent Publication 87/05297, Johnston et al., published Sep. 11, 1987, incorporated herein by reference. Such salts are made by methods known to one of ordinary skill in the art. It is recognized that the skilled artisan may prefer one salt over another for improved solubility, stability, formulation ease, price and the like. Determination and optimization of such salts is within the purview of the skilled artisan""s practice. Preferred cationic salts include the alkali metal salts (such as sodium and potassium), and alkaline earth metal salts (such as magnesium and calcium) and organic salts. Preferred anionic salts include the halides (such as chloride salts), sulfonates, carboxylates, phosphates, and the like. Clearly contemplated in such salts are addition salts that may provide an optical center where once there was none. For example, a chiral tartrate salt may be prepared from the compounds of the invention. This definition includes such chiral salts.
xe2x80x9cPhenylxe2x80x9d is a six-membered monocyclic aromatic ring which may or may not be substituted with from about 1 to about 4 substituents. The substituents may be substituted at the ortho, meta or para position on the phenyl ring, or any combination thereof. Preferred phenyl substituents include: halo, cyano, lower alkyl, heteroalkyl, haloalkyl, phenyl, phenoxy or any combination thereof. More preferred substituents on the phenyl ring include halo and haloalkyl. The most preferred substituent is halo.
Compounds
The invention involves compounds having the following structure: 
In Formula I above, R1 is H or lower alkyl. Preferred R1 is lower alkyl. More preferred R1is methyl and ethyl. The most preferred R1 is methyl.
In Formula I above, R2 is H, alkyl, heteroalkyl, carbocyclic aliphatic ring, heterocyclic aliphatic ring, aromatic ring, or heteroaromatic ring. Preferred R2 is H and alkyl. More preferred R2 is H and lower alkyl.
In Formula I above, X is O or S. Preferred X is O.
In Formula I above, Y is O, S or NH. Preferred Y is O and NH. The most preferred Y is O.
In Formula I above, V is C4 alkyl or M4 heteroalkyl. Preferred V is C4 alkyl. More preferred V is unsubstituted C4 alkyl.
In Formula I above, a is single bond, cis double bond, or trans double bond.
In Formula I above, b is single bond, trans double bond, or triple bond.
In Formula I above, when a is single bond, W is OH or N(R3)(OR4); wherein R3 is H, lower alkyl, or lower heteroalkyl and R4 is H, lower alkyl, or lower heteroalkyl. Preferred R3 is H and lower alkyl. More preferred R3 is H and methyl. Preferred R4 is H and lower alkyl. More preferred R4 is H and methyl. The most p referred R4 is H.
In Formula I above, when a is cis double bond or trans double bond, W is N(OR4); wherein R4, is as defined above.
In Formula I above, Z is C1 alkyl, M1 heteroalkyl, Cm alkyl-G"", Mn heteroalkyl-G"", Cp alkyl-Gxe2x80x9d, or Mq heteroalkyl-Gxe2x80x9d; wherein 1 is an integer from about 3 to about 7, preferably from about 4 to about 7; m is an integer from 0 to about 5, preferably from about 1 to about 4, more preferably still about 2 or 3, most preferably 2; n is an integer from about 2 to about 5, preferably about 2 or 3; p is an integer from 0 to about 3, preferably 0 to about 2, more preferably 0 or about 1; q is 2 or 3, preferably 2; G"" is monocyclic carbocyclic aliphatic ring, monocyclic heterocyclic aliphatic ring, monocyclic aromatic ring, or monocyclic heteroaromatic ring; Gxe2x80x9d is bicyclic carbocyclic aliphatic ring, bicyclic heterocyclic aliphatic ring, bicyclic aromatic ring, or bicyclic heteroaromatic ring. Preferred G"" is monocyclic aromatic ring or monocyclic heteroaromatic ring. Preferred Gxe2x80x9d is bicyclic aromatic ring or bicyclic heteroaromatic ring.
The invention includes pharmaceuticallyxe2x80x94acceptable salts, or biohydrolyzable amides, esters, or imides of the above structure. The invention also includes optical isomers, diastereomers and enantiomers of the above structure. Thus, at all stereocenters where stereochemistry is not defined (e.g. C11 and C15), both epimers are envisioned. Preferred stereochemistry at C11 and C15 mimics that of naturally occurring PGF2a.
It has been discovered that the novel PGF analogs of the subject invention are useful for treating bone disorders, especially those that require a significant increase in bone mass, bone volume, or bone strength. Surprisingly, the compounds of the subject invention have been found to provide the following advantages over known bone disorder therapies: (1) An increase trabecular number through formation of new trabeculae; (2) An increase in bone mass and bone volume while maintaining a more normal bone turnover rate; and/or (3) An increase in bone formation at the endosteal surface without increasing cortical porosity.
In order to determine and assess pharmacological activity, testing of the subject compounds in animals is carried out using various assays known to those skilled in the art. For example, the bone activity of the subject compounds can be conveniently demonstrated using an assay designed to test the ability of the subject compounds to increase bone volume, mass, or density. An example of such assays is the ovariectomized rat assay.
In the ovariectomized rat assay, six-month old rats are ovariectomized, aged 2 months, and then dosed once a day subcutaneously with a test compound. Upon completion of the study, bone mass and/or density can be measured by dual energy x-ray absorptometry (DXA) or peripheral quantitative computed tomography (pQCT), or micro computed tomography (mCT). Alternatively, static and dynamic histomorphometry can be used to measure the increase in bone volume or formation.
Pharmacological activity for glaucoma can be demonstrated using assays designed to test the ability of the subject compounds to decrease intraocular pressure. Examples of such assays are described in the following reference, incorporated herein: C. liljebris, G. Selen, B. Resul, J. Sternschantz, and U. Hacksell, xe2x80x9cDerivatives of 17- Phenyl-18,19,20-trinorprostaglandin F2xcex1Isopropyl Ester: Potential Antiglaucoma Agentsxe2x80x9d, Journal of Medicinal Chemistry, Vol. 38 No. 2 (1995), pp. 289-304.
The following non-limiting examples illustrate the compounds of the present invention: